1. CLINICAL PROTOCOL DEVELOPMENT

2. What is the study hypothesis?
What’s The Question?
What is the study hypothesis?

3. What’s The Question? What’s the outcome? What’s the intervention?
When and for how long?
For whom?
How many participants are needed?
How can we optimize potential benefit (and what we learn) while minimizing potential harm?

4. Answering the Question
Response variable selection and measurement
Defining the intervention
Study design
Eligibility criteria
Sample size estimate
Patient management procedures
Monitoring for safety and benefit
Data analysis approaches

5. Response Variable Selection
“Dose ranging”
Biologic activity
Biomarker
Understand mechanism
Surrogate outcome
Toxicity
Condition/vector/gene interaction
Feasibility for larger study
Clinical outcome

6. Response Variable Criteria
Well defined
Stable
Reproducible
Unbiased
Ascertainable in all participants
Adequately address study hypothesis

7. Defining the Intervention
Dose/dosing schedule
Vector
Route of delivery
Method of preparation

8. Study Design Uncontrolled Controlled Before/after Historical
Concurrent, not randomized
Randomized

9. Comparing Treatments Fundamental principle
Groups must be alike in all important aspects and only differ in the intervention each group receives
In practical terms, “comparable treatment groups” means “alike on the average”
Randomization
Each participant has the same chance of receiving any of the interventions under study
Allocation is carried out using a chance mechanism so that neither the participant nor the investigator will know in advance which will be assigned
Blinding
Avoidance of conscious or subconscious influence
Fair evaluation of outcomes

10. Non-randomized Trials May Be Appropriate
Early studies of new and untried therapies
Uncontrolled early phase studies where the standard is relatively ineffective
Investigations which cannot be done within the current climate of controversy (no “clinical equipoise”)
Truly dramatic response

11. Advantages of Randomized Control Clinical Trial
1. Randomization "tends" to produce comparable groups
2. Randomization produces valid statistical tests

12. Disadvantages of Randomized Control Clinical Trial
1. Generalizable Results?
Participants studied may not represent general study population.
2. Recruitment
Hard
3. Acceptability of Randomization Process
Some physicians will refuse
Some participants will refuse
4. Administrative Complexity

13. Study Population
Subset of the general population determined by the eligibility criteria
General population
Eligibility criteria
Study population
Enrollment
Study sample
Observed

14. Eligibility Criteria State in advance Consider
Potential for effect of intervention
Ability to detect that effect
Safety
Ability for true informed consent

15. Sample Size (1) The study is an experiment in people
Need enough participants to answer the question
Should not enroll more than needed to answer the question
Sample size is an estimate, using guidelines and assumptions

16. Sample Size (2) Approaches for early phase studies
Dose escalation schemes
Decision that intervention is unlikely to be effective in x% of participants
Decision that intervention could be effective in x% of participants
Standard ways of estimating for phase III

17. Sample Size (3) Assumptions depend on Nature of condition
Desired precision of answer
Availability of alternative treatments
Knowledge of intervention being studied
Availability of participants

18. Regular Follow-up Routine Procedures (report forms)
Interviews
Examinations
Laboratory Tests
Adverse Event Detection/Reporting
Quality Assurance

19. Contingency Plans Patient management
Evaluation and reporting to all relevant persons and groups
Data monitoring plans
Protocol amendment or study termination

20. Data Analysis (1) Occurrence of event Time to event
Mean level of response
Duration of response

21. Data Analysis (2) Intention-to-treat Explanatory Subgroups
Adjusted vs. Unadjusted

22. Data Analysis (3) Specify in advance Exploratory Primary Secondary
Other
Statistical approach
Exploratory

23. Clinical Protocol (1) Background/Justification Objectives
--Where we are in the field
--What the study will add that is important
Objectives
--Primary hypothesis
--Secondary hypotheses
--Other

24. Clinical Protocol (2) Study Design and Methods
--Type of study, comparison
--Inclusion and exclusion criteria
--Description of intervention (what, how)
--Concomitant therapy
--Examination procedures (baseline, follow-up, outcome assessment)
--Intervention assignment procedure

25. Clinical Protocol (3) Monitoring and Management
--Data and safety monitoring
--Adverse event assessment, reporting
--Contingency procedures
--Withdrawal criteria

26. Clinical Protocol (4) Statistics Participant protection issues
--Sample size
--Stopping guidelines
--Analysis plans
Participant protection issues

27. Summary Protocol lays out who, what, why, when, where, how
Safeguards participants
Safeguards study integrity
Midcourse changes are often appropriate (even necessary)